title: Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches for human disease.
abstract: The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
authors.affiliation: The Ohio State University Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH;
authors.forename: Kelsie M
authors.initials: KM
authors.lastname: Bernot
authors.forename: John S
authors.initials: JS
authors.lastname: Nemer
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Zorko
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Dickerson
authors.forename: Mengzi
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: McConnell
authors.forename: Elshafa H
authors.initials: EH
authors.lastname: Ahmed
authors.forename: Maura R
authors.initials: MR
authors.lastname: Muñoz
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Siebenaler
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Marcucci
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Mundy-Bosse
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Brook
authors.forename: Sabrina
authors.initials: S
authors.lastname: Garman
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D019175:DNA Methylation; D004337:Drug Carriers; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008081:Liposomes; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004337:Drug Carriers; D008081:Liposomes; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012334:RNA, Neoplasm; D051788:Myeloid-Lymphoid Leukemia Protein; D000069286:Bortezomib; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3